Pyrazine derivatives as modulators of tyrosine kinases

Details Pyrazine derivatives as modulators of tyrosine kinases Pyrazine derivatives as modulators of tyrosine kinases

2001-09-19

2004-03-23

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C514S255050, C544S120000, C544S357000, C544S405000

Reexamination Certificate

active

06710048

ABSTRACT:

The present invention provides pyrazine derivatives that inhibit tyrosine kinase activity. Certain pyrazine derivatives are selective inhibitors of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase. The present invention also provides pharmaceutical formulations containing the pyrazine derivatives and methods for use of these formulations as anti-tumor agents, and to treat diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis.
BACKGROUND OF THE INVENTION
Angiogenesis plays a role in various processes including development of the vasculature, wound healing and maintenance of the female reproductive system. Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis. Solid-tumor cancers, in particular, are dependent on angiogenesis for their growth. The vascular endothelial growth factors (VEGFs) are mediators of both normal and pathologic angiogenesis. VEGF transmits signals into cells through their cognate receptors, which belong to the receptor tyrosine kinase (RTK) family of transmembrane receptors. These receptors are tripartite, consisting of an extracellular ligand-binding domain, a transmembrane domain, which anchors the receptor in the membrane of the cell, and an intracellular tyrosine kinase domain. One subfamily of RTKs comprises the receptors Flt1/VEGF-R1 and KDR/Flk1/VEGF-R2, which bind VEGFs. Binding of the VEGF ligand to the receptor results in stimulation of the receptor tyrosine kinase activity and transduction of biological signals into the cell. The KDR/Flk1/VEGF-R2 receptor mediates the biological activities of mitogenesis and proliferation of endothelial cells while the Flt1/VEGF-R1 receptor mediates functions such as endothelial cell adhesion. Inhibition of KDR/Flk1/VEGF-R2 signalling has been shown to inhibit the process of angiogenesis. Inhibitors of this receptor are likely useful in controlling or limiting angiogenesis.
SUMMARY OF THE INVENTION
The present invention provides pyrazine derivative compounds that display activity as kinase inhibitors of the formula:
where the substituents are defined herein. These pyrazine derivatives are useful as kinase inhibitors; particularly, as inhibitors against the kinase domain of the Vascular Endothelial Growth Factor Receptor (VEGF-R), inhibiting the activity of the VEGF receptor in vitro and in vivo.
In a preferred embodiment, the invention relates to compounds of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein
R
1
is selected from the group consisting of cycloalkyl, heterocyclyl, biheterocyclyl, aryl, biaryl, heteroaryl and biheteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, lower alkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, aminoalkyl, aminoalkylamino, di(alkyl)amino, di(alkyl)aminoalkyl, di(alkyl)aminoalkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), aminosulfonyl, aminosulfonylalkyl, alkylaminosulfonyl, alkylaminosulfonylalkyl, di(alkyl)aminosulfonyl, di(alkyl)aminosulfonylalkyl, carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, trihalo substituted lower alkyl and trihalo substituted lower alkoxy;
A is selected from the group consisting of —N(R
4
)(CH
2
)
x
—, —O(CH
2
)
x
—, —S(CH
2
)
x
—, —SO
2
(CH
2
)
x
—, —SO
2
N(CH
2
)
x
—, —NSO
2
(CH
2
)
x
—, —N(R
4
)(CH
2
)
x
—, —N(R
4
)(CH
2
)
1-4
NH(CH
2
)
x
—, —N(R
4
)CONH(CH
2
)
x
— and —N(R
4
)CNNH(CH
2
)
x
—; wherein x is an integer from 0 to 4;
R
4
is selected from the group consisting of H, lower alkyl, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, lower alkenyl, alkenyl, aryl and heteroaryl; wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, alkyl, lower alkyl, alkoxy, lower alkoxy, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy;
R
2
is selected from the group consisting of heteroaryl and biheteroaryl optionally substituted with 1 to 2 substituents independently selected from R
7
and 1 substituent selected from R
8
;
R
7
is selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy;
R
8
is selected from the group consisting of alkyl, OH, hydroxyalkyl, halogen, cyano, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, alkylcarbonylamino, alkylcarbonyl, alkoxycarbonyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, O(CH
2
)
n
R
5
, O(CH
2
)
n
O(CH
2
)
m
R
5
, O(CH
2
)
n
CH[(CH
2
)
m
R
5
]
2
, O(CH
2
)
n
N[(CH
2
)
m
R
5
]
2
, OCON[(CH
2
)
m
R
5
]
2
, NH(CH
2
)
n
R
5
, NH(CH
2
)
n
CH(R
5
)
2
, NH(CH
2
)
n
SO
2
(CH
2
)
m
R
5
, NH(CH
2
)
n
O(CH
2
)
m
R
5
, NH(CH
2
)
n
OCH[(CH
2
)
m
R
5
]
2
, NH(CH
2
)
n
O(CH
2
)
m
O(CH
2
)
m
R
5
, NH(CH
2
)
n
N[(CH
2
)
m
R
5
]
2
, NH(CH
2
)
n
SO
2
NH(CH
2
)
m
R
5
, NH(CH
2
)
n
CH(OH)(CH
2
)
m
R
5
, NH(CH
2
)
n
CH(OH)(CH
2
)
m
OR
5
, NH(CH
2
)
n
CH(OH)(CH
2
)
m
N[(CH
2
)
m
R
5
]
2
, NH(CH
2
)
n
CO(CH
2
)
m
N[(CH
2
)
m
R
5
]
2
, NH(CH
2
)
n
CO
2
(CH
2
)
m
R
5
, NH(CH
2
)
n
CO(CH
2
)
m
SO
2
NH(CH
2
)
m
R
5
, NHCO(CH
2
)
n
CH(R
5
)
2
, NHCO(CH
2
)
n
R
5
, NHCO(CH
2
)
n
O(CH
2
)
m
R
5
, NHCO(CH
2
)
n
O(CH
2
)
m
O(CH
2
)
m
R
5
, NHCO(CH
2
)
n
O(CH
2
)
m
CO(CH
2
)
m
R
5
, NHCO(CH
2
)
n
N[(CH
2
)
m
R
5
]
2
, CONH(CH
2
)
n
O(CH
2
)
m
R
5
, and CONH(CH
2
)
n
N[(CH
2
)
m
R
5
]
2
; wherein n is an integer from 0 to 6 and m is an integer from 0 to 4; with the proviso, that m is at least 1 when R
5
is selected from the group consisting of OH, amino, alkylamino and di(alkyl)amino;
R
5
is selected from the group consisting of H, OH, lower alkyl, amino, alkylamino, di(alkyl)amino, aryl, heteroaryl, biheteroaryl and heterocyclyl; wherein aryl, heteroaryl and heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, lower alkyl, acyl, carboxyl, aryl (optionally substituted with 1 to 5 halogen substituents), OH, halogen, cyano, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl and aminosulfonylalkyl; and, wherein heterocyclyl is further optionally substituted with 1 to 3 oxo substituents; and, R
3
is selected from the group consisting of H, alkyl, lower alkyl, alkoxy, lower alkoxy, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(h

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